Improvements in vaccines against influenza that increase breadth and duration of protection would improve worldwide ability to combat seasonal changes in influenza viruses (drift) and appearance of new pandemic strains (shift). This study aims to develop new platforms and vaccination strategies against influenza. Nanoparticles, nucleic acids and adenoviral vectored vaccines have been developed against multiple seasonal and pandemic strains of influenza, including recently identified H1N1, H7N9, H5N1 avian flu and seasonal flu. In addition, studies are ongoing to identify and optimize vaccine antigens to present conserved regions of the influenza virus hemagglutinin (HA) in order to develop a vaccine that provides more universal protection. These include nanoparticle display of both group 1 and group 2 influenza HA stabilized stem trimers, as well as conserved epitopes of the HA head. Testing has been conducted to evaluate candidates, as well as adjuvants to boost immune response, and determine the optimal strategies for immunization. Several candidates showed promising results and testing is continuing, using DNA and DNA prime with inactivated vaccine boost or nano particles displaying full length, stem, and/or receptor binding domain HA antigens. Six cycles of iterative structure-based design resulted in a stabilized version of the HA stem based on H1N1 A/New Caledonia/20/1999. Soluble versions of these immunogens were created to test immunogenicity in mouse models, as well as to co-crystallize with stem-binding monoclonal antibodies. Immunization with these nanoparticles induces homologous and heterologous binding antibodies in mice and ferrets, but low levels of neutralizing antibodies. Despite this relative lack of neutralization, immunization elicits complete protection in mice and partial protection in ferrets from heterologous, H5N1 lethal influenza challenge. Passive transfer of IgG from mice immunized with H1-SS-NP protects mice from lethal H5 challenge, suggesting protection is humorally mediated. Further studies to determine the mechanism of protection are underway, as well as efforts to improve the group 1 immunogen to increase neutralizing responses. Group 2 designs have also been advanced into in vitro and animal studies. In addition, collaborations to develop RNA vaccine platforms for delivery are underway. Final preparations are ongoing for the first influenza HA nanoparticle vaccine human clinical trial.